PROJECT SUMMARY/ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne emerging pathogen that causes severe and often fatal hemorrhagic fever in humans across a broad geographic range that includes more than 30 countries. The NIAID lists CCHFV as a Category A priority pathogen, a biological agent that poses the highest risk to national security and public health. CCHF is of particular importance to public health as there are no licensed vaccines or treatments available for use in humans, and because of the concern that the virus could be used as an agent of biological terrorism. The goal of this project is to develop a monoclonal antibody-based postexposure treatment as a potential medical countermeasure that can provide protection across all six genetically distinct clades of CCHFV. Monoclonal antibodies will be compared in vitro to select candidates that protect against CCHFVs representing all major M segment clades. The most promising antibodies will then be tested using the STAT-1 knockout mouse model for their ability to protect against disease when the antibodies are given following challenge with CCHFV. Dosing and treatment regimens will then be optimized. The lead candidate antibody will be evaluated for its ability to protect nonhuman primates from CCHFV disease when administered after exposure. This proposal will draw together the expertise needed to develop lead anti- CCHFV mouse monoclonal antibodies chimerized with human constant regions, as well as to develop and optimize fully human anti-CCHF monoclonal antibodies.